Journal Article

Rapid reversal of interleukin-6-dependent epithelial invasion in a mouse model of microbially induced colon carcinoma

Theofilos Poutahidis, Kevin M. Haigis, Varada P. Rao, Prashant R. Nambiar, Christie L. Taylor, Zhongming Ge, Koichiro Watanabe, Anne Davidson, Bruce H. Horwitz, James G. Fox and Susan E. Erdman

in Carcinogenesis

Volume 28, issue 12, pages 2614-2623
Published in print December 2007 | ISSN: 0143-3334
Published online August 2007 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgm180
Rapid reversal of interleukin-6-dependent epithelial invasion in a mouse model of microbially induced colon carcinoma

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Chronic inflammation of mucosal surfaces renders them increasingly susceptible to epithelial cancers both in humans and mice. We have previously shown that anti-inflammatory CD4+CD45RBloCD25+ regulatory (Treg or TR) lymphocytes down-regulate inflammation and block development of bacteria-triggered colitis and colorectal cancer (CRC) in 129/SvEv Rag2−/− mice. Interestingly, TR cells collected from Interleukin (IL)-10-deficient cell donors not only failed to suppress carcinogenesis but instead promoted invasive mucinous colonic carcinoma with a strong gender bias expressing in male mice. We found we show that peritoneal invasion in this model is dependent on pleiotropic cytokine IL-6. Mucinous carcinoma arose rapidly and consistently after treatment with IL10−/− TR cells, which were found to express Foxp3+ and localize throughout tumor tissue. Carcinogenesis was rapidly reversible with transfer of wild type IL10-competent TR cells. Likewise, treatment with IL10-Ig fusion protein was sufficient to revert the lesions histologically, and restore inflammatory cytokine and oncogene expression to base line levels. These studies indicate an essential role for IL 6 in this CRC phenotype. Furthermore, immune-competent TR cells were important not only for preventing pathology but also for constructive remodeling of bowel following tumorigenic microbial insults. These data provide insights into etiopathogenesis of inflammation-associated epithelial invasion and maintenance of epithelial homeostasis.

Journal Article.  7568 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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